Nonvisual indication of an unwanted chemical in an ingestible substance

ABSTRACT

Methods and systems for detecting and indicating the presence of undesirable substances in ingestible substance such as food or beverages. More specifically, systems and methods for nonvisually and concealably indicating and detecting the presence of unwanted or undesired drugs in beverages and/or food.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/658,018, filed Mar. 13, 2015 and entitled “Nonvisual Indication of anUnwanted Chemical in an Ingestible Substance”, which application is acontinuation of U.S. patent application Ser. No. 14/517,730, filed Oct.17, 2014, and issued Mar. 17, 2015 as U.S. Pat. No. 8,978,468 andentitled “Nonvisual Indication of an Unwanted Chemical in an IngestibleSubstance”, which application is a continuation-in-part of U.S. patentapplication Ser. No. 12/907,969, filed Oct. 19, 2010 and entitled“Nonvisual Indication of an Unwanted Chemical in an IngestibleSubstance”, which in turn claims the benefit under 35 U.S.C. § 119(e) ofU.S. Provisional Patent Application Ser. No. 61/253,048, filed Oct. 19,2009 and entitled “Methods and Systems for Performing a Concealed Testto Determine the Presence of an Unwanted Drug in a Beverage”, thedisclosures of each of which are herein incorporated by reference.

BACKGROUND

The present invention relates to methods and systems for detecting andindicating the presence of undesirable substances in ingestiblesubstance such as food or beverages. More specifically, the inventionrelates to systems and methods for nonvisually and concealablyindicating and detecting the presence of unwanted or undesired drugs ina beverage or food.

Certain drugs, sometimes referred to as “date rape drugs,” have beenused to facilitate sexual assaults on unsuspecting victims. Typicallythe drug is surreptitiously placed in the intended victim's beverage orfood. This is a relatively easy process because this class of drugtypically provides little or no indication of its presence, creatinglittle or no color change, detectable smell, or change in flavor in thedrugged substance that could detected by the intended victim. Onceconsumed, the drugs typically used for this purpose can create weakness,confusion, and/or unconsciousness in the victim, who typically has nomemory of what transpired while they were drugged. Some of these drugs,when combined with alcohol consumption, may exhibit an even morepronounced sedating effect.

While the victim is unconscious or disoriented, they may be subjected tosexual assault, theft, or other abuses by the person who drugged them.

Some pharmaceuticals which have been used as date rape drugs includeflunitrazepam (trade name ROHYPNOL, and street name “roofie”),gamma-hydroxybutyric acid (or GHB), and ketamine. Similar acting drugsmay also be used as date rape drugs, such as clonazepam (trade nameKLONOPIN in the U.S. and RIVOTRIL in Mexico), alprazolam (trade nameXANAX), and other benzodiazepines including temazepam (trade nameRESTORIL) and midazolam.

Currently available tests for the detection of such drugs focus oncreating a visible indicator that that the drug is present. Selectedtesting methods and systems are described in (a) U.S. Pat. Nos.4,992,296; 5,457,054; 6,153,147; 6,703,216; 6,713,306; and 7,238,533;(b) U.S. Patent Application Nos. US2001/0046710; US2003/0026731;US2003/0224474; US2004/0146429; US2007/0065338; US2007/0099300;US2008/0006600; US2008/0102482; and US2009/0196675; (c) PCT PatentApplication No. WO2005/059541; and (d) U.K. Patent No. 2436362, all ofwhich are incorporated herein by reference.

The above types of tests are typical, in that they involve a testerdevice that, when exposed to a liquid, exhibits a visual color changewhen a target drug is present in the liquid. See for example U.S. Pat.No. 7,238,533, which discloses a color change in applied finger nailpolish; U.S. Patent Application Publication No. 2004/0146429, whichdiscloses an embedded so-called colorimetric indicator in a porousmaterial used as a cocktail napkin, coaster, placemat, menu, matchbook,drink carrier, flyer, coupon, personal test kit or business card; andU.S. Patent Application Publication No. 2007/0099300, which discloses acolor change on a straw. These tests, however, may not be readilyconcealable, as each test requires a visual analysis in order todetermine the results of the test. Opportunities for testing maytherefore be limited in a social setting and in the presence of theperson who is suspected of placing an unwanted drug in a beverage.

What is needed is a test system that can verify the presence or absenceof a target drug in a food or beverage without requiring a visualevaluation, so that the person suspected of tampering with the food orbeverage need never know that they are under suspicion.

BRIEF SUMMARY

In one embodiment, the invention includes a non-visual verificationmethod that includes selecting an ingestible substance, using a detectoron the selected, ingestible substance, and non-visually indicatingwhether a target substance is present in the ingestible substance.

In another embodiment, the invention includes a non-visual verificationmethod that includes selecting an ingestible substance; making adetector for non-visual display of whether a target substance is presentin the selected, ingestible substance; operating the detector andnon-visually indicating whether a target substance is present in theingestible substance.

In yet another embodiment, the invention is characterized as anon-visual verification system, where the non-visual verification systemincludes a non-visual, sensing mechanism constructed to verify whether atarget drug is present in an ingestible substance by producing anon-visual indicator that can be understood by a user.

In yet another embodiment, the invention is characterized as anon-visual verification device, where the non-visual verification deviceincludes a non-visual, sensing component constructed to verify whether atarget drug is present in an ingestible substance by producing anon-visual indicator that can be understood by a user.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

FIG. 1 is a flowchart depicting a non-visual verification method,according to a selected embodiment of the invention.

FIG. 2 is a flowchart depicting a non-visual verification method,according to another selected embodiment of the invention.

FIG. 3 is a schematic depiction of a non-visual verification system,according to yet another selected embodiment of the invention.

DETAILED DESCRIPTION

The present invention includes systems and methods for performing anon-visual test to determine the presence of a target substance in aningestible substance. In particular, the invention includes systems andmethods for performing a non-visual test to determine the presence of atarget substance in an ingestible substance, where the target substancemay be indicated both non-visually and concealably.

One embodiment of the present method is depicted as flowchart 10 inFIG. 1. The method includes selecting an ingestible substance, at 12;using a detector on the selected, ingestible substance, at 14; andnon-visually indicating whether a target substance is present in theingestible substance, at 16.

A second embodiment of the present method is depicted as flowchart 18 inFIG. 2. The method of FIG. 2 includes selecting an ingestible substance,at 20; making a detector for non-visual display of whether a targetsubstance is present in the selected, ingestible substance, at 22; andoperating the detector and non-visually indicating whether a targetsubstance is present in the ingestible substance, at 24.

The disclosed methods may be performed using a non-visual verificationsystem 26, as depicted schematically in FIG. 3. The non-visualverification system includes a sensing component 28, and an indicatingcomponent at 30. The non-visual verification system optionally furtherincludes a processor 30, as will be discussed below.

The non-visual verification system may be used to test an ingestiblesubstance, prior to consumption, for one or more specific targetsubstances. That target substance(s) is typically an unwanted orundesired substance, such as a drug or a toxin. More particularly, thetarget substance may be a drug intended to confuse or sedate theconsumer. Selected embodiments of the target substance includeflunitrazepam, gamma-hydroxybutyric, ketamine, clonazepam, alprazolam,temazepam, and midazolam, without limitation.

The non-visual verification system is typically configured so that theingestible substance may be tested for the target substance concealably.As used herein, the test is administered concealably where theingestible substance may be tested for the target substance withoutalerting bystanders or companions that the test has been administered,or revealing the results of the test.

The non-visual verification system includes a sensing component, wherethe selected ingestible substance interacts with the system. The sensingcomponent may be as simple as a molecule or a molecular array thatincorporates one or more binding sites that are complementary to thetarget substance, such that binding the target substance resultsdirectly or indirectly in a non-visual response.

The ingestible substance to be tested may be any solid, semi-solid, orliquid that is intended for ingestion. The ingestible substance may alsobe a food or beverage. In one aspect of the invention, the ingestiblesubstance is a liquid or semi-liquid, to facilitate detection of thetarget substance by chemical or physical interaction. The ingestiblesubstance may also include chewing gum, toothpaste, and other substancesthat may be placed in the mouth, but not be intended to be swallowed.

The non-visual verification system typically incorporates an indicatingcomponent capable of indicating the presence of the selected targetsubstance via a non-visual indication. In one embodiment, the indicatingcomponent is directly coupled to the sensing component, such as viamolecular recognition, where binding the target substance triggers amolecular modification that produces that desired non-visual indication,such as via a change in flavor, odor, or texture.

In one particular embodiment, the non-visual verification system maycorrespond to an indicator substance that is selectively reactive towardthe target substance (the sensing component), and produces anidentifiable flavor compound in the presence of the target substance(the indicating component). Preferably, such substances react with thedesired target substance with both selectivity and specificity, so as toavoid false positives. For example, the interaction between an indicatorsubstance and the target substance may be similar to that of specificbinding pairs. The indicator substance may be designed so that bindingthe target substance triggers a molecular rearrangement of the indicatorsubstance, creating a distinct flavor change. Alternatively, or inaddition, binding the target substance may trigger the release of one ormore small molecules that are then detectable by flavor or odor.

Such an indicator substance may be utilized by placement in the user'smouth, or by placing a component of the non-visual verification systemthat includes the indicator substance in the user's mouth. Selectedembodiments of the indicator substance may produce a bitter, orotherwise identifiable, taste to the user. The indicator substance mayinclude more than one constituent element, and may correspond to anycomposition, element, material, reagent, or solution, or combinationthereof, that is suitable for producing such an identifiable or bittertaste upon reaction with the target substance. In one embodiment, thenon-visual verification system incorporates multiple indicatorsubstances, each configured to react selectively with one or more targetsubstances to produce a range of individually identifiable flavors. Sucha multi-target system may be useful for the detection of multipletargets of interest simultaneously.

Where the indicating component is intended to produce a non-visualindication that is a flavor, the indicating component may be present ona strip of paper, a dissolvable strip of material, a saliva-dissolvablematerial, or a chewing gum-type of material, which a user may put intheir mouth prior to ingesting the ingestible substance. The substancemay also be formulated as a liquid additive packaged in a smallcontainer with a dispenser such as a dropper/pipette so that the usercan place a drop of the liquid additive in/on the beverage or food,respectively.

An indicator substance configured to create an identifiable or bittertaste when in contact with target substance may be delivered to the userin any suitable form, such as through a pill, a readily-dissolvabletablet, or through a liquid solution. The indicating substance can alsobe, or be impregnated in, any chewable or edible item that resembles acommon beverage or food item, such as a stick or piece of gum, breathmint, mint, candy, such as those candies sold under the federallyregistered trademark TIC TAC, etc. The substance can therefore be usedopenly in a manner that would not otherwise alert others that the useris performing a test for the presence of unwanted drugs in a beverage orfood item. Alternatively, the substance may be added to the beverage orfood itself to produce an identifiable and/or bitter taste.

In some embodiments, the test may include a user placing anon-visual-detector substance in his or her mouth, then drinking thebeverage or eating the food in question. Thenon-visual-detector-detector substance may cause the user to have apre-selected indicator taste. For example, a user may place adissolvable strip of material in their mouth to moisten and/or dissolvethe strip, thereby releasing the substance. The substance may then coatall or a portion of the interior of the user's mouth, including thetaste buds, with the substance, so that the test may be performed bysubsequently sipping, ingesting, or tasting a small portion of thesuspected beverage or food. The results of the test are therefore fullyconcealed from others and only known to the taster.

All of the compositions, substances and methods disclosed herein can bemade and executed without undue experimentation in light of the presentdisclosure. While the compositions, substances and methods of thisdisclosure have been described in terms of preferred embodiments, itwill be apparent to those of skill in the art that variations may beapplied to the compositions/substances, and in the steps or in thesequence of steps of the method described herein without departing fromthe concept, spirit and scope of the present disclosure. Morespecifically, it will be apparent that certain substances that are bothchemically and physiologically related may be substituted for thesubstances described herein while the same or similar results would beachieved. All such similar substitutes and modifications apparent tothose skilled in the art are deemed to be within the spirit, scope andconcept of the present disclosure.

In an alternative embodiment, the non-visual verification system maycorrespond to a device that incorporates a sensing component and anindicating component. In this embodiment, the sensing component mayincorporate a sample chamber or receptacle, where an aliquot of theingestible substance to be tested may be inserted for sensing.Alternatively, the sensing component may be configured to be insertedinto the ingestible substance, such as a dipstick, test strip, orcapillary tube. In one embodiment, the sensing component may include aremovable sample collector that is configured to be removed from thenon-visual verification system and used to collect an aliquot of theingestible substance of interest. The sample collector may then bereattached or reinserted into the non-visual verification system foranalysis. Alternatively, the non-visual verification system mayincorporate one or more stages of sample treatment, such as by theaddition of water or other solvent, one or more reagents, and optionallyincluding maceration or mixing in order to facilitate detection of atarget substance.

The sensing component may incorporate any of a variety of chemicalsensors, electrochemical sensors, spectrometric sensors, pH sensors, andthe like. Highly selective detection may be accomplished via the use ofenzyme-linked-bound antibodies that bind specifically to selected targetsubstances, and then generate a detectable response via an enzymaticreaction (for example as used in ELISA assays). The sensing componentmay include only one type of chemical sensor, or may incorporate aplurality of chemical sensors to permit detection of more than onetarget substance.

Alternatively, the sensing component may utilize one or moremicrofluidic systems to analyze an ingestible substance for the targetsubstance. Microfluidics permit the manipulation of extremely smallvolumes of analyte utilizing microfluidic channels having diameters onthe order of around 100 nm to several hundred μm. Microfluidic methodsinclude a wide variety of analytical methods, leading to the descriptionof microfluidic methods as ‘labs-on-a-chip’.

Where the non-visual verification system incorporates distinct sensingand indicating components, the non-visual verification system may alsoincorporate a processor 30, as shown in FIG. 3. The processor maycorrespond to one or more chips, transistors, and processing unitsconfigured to receive data originating from the sensing component,evaluating the sensing data, and triggering the indicator component tocreate the appropriate non-visual indication.

Where the indicating component incorporates a physical indicator thatresponds to instructions from the processor, the indicating componentmay generate any of a variety of possible non-visual indications,including smell, touch and sound. For example, the indicating componentmay be configured to release an appropriate fragrance upon detection ofa particular target substance. Alternatively, the indicating componentmay include a tactile indicator portion, either affixed to thenon-visual verification system, or configured to be used remotely. Thetactile indicator may be configured to alert the user by vibrating,administering a gentle electrical shock to the user's skin, or applyinglocalized heating, for example. When used remotely, the tactileindicator may take the form of a patch or adhesive button that can beremovably affixed to the user's skin, for example under clothing, andthen activated by the non-visual verification system. Remotecommunication between the non-visual verification system and the tactileindicator may be accomplished using radio transmissions, among othermethods. A sound indicator could also be used that responds to, forexample, a chemical reaction by emitting a sound to indicate that thetarget substance is present in the ingestible substance.

EXAMPLES

The following example describes an exemplary screening process for anappropriate non-visual-detector substance. This example is intended forillustration and should not be interpreted as limiting the entire scopeof the present disclosure.

Example 1: Designing a Detector Substance for ROHYPNOL

Flunitrazepam (ROHYPNOL, NARCOZEP) is a benzodiazepine derivative, andthus contains the core chemical structure characteristic of allbenzodiazepines. Flunitrazepam is specifically classed as anitro-benzodiazepine, and it is the fluorinated methylamino derivativeof nitrazepam, another benzodiazepine derivative. Flunitrazepam ischaracterized by the presence of a fluoro substituent attached to apendant phenyl substituent.

A first criteria for an appropriate non-visual-detector substance isthat the reagent should be safe for human consumption at effectiveconcentrations. A second criteria is that it possess an appropriatecross-reactivity with flunitrazepam. A third criteria is that non-visualindicators such as taste and/or smell associated with the resultingadduct compound should be readily detectable by an animal or humanconsumer of the adduct compound. A fourth criteria is that thenon-visual indicators are readily distinctive to an animal or humanconsumer.

Safe for Consumption

Reactants are to be consumed and, as a result, they must be safe forhuman consumption when present in the final product. To ensure thatreagents are safe for human consumption, only those compounds present inthe EAFUS (Everything Added to Food in the United States) database andGRAS (Generally Recognized as Safe) database according to the U.S. Foodand Drug Administration are considered as candidates for detectorsubstances.

Appropriate Cross-Reactivity

Selected compound databases were screened by evaluating their potentialreactivity towards flunitrazepam. Substances that reacted withflunitrazepam only under strong reaction conditions or in the presenceof catalysts were deemed unsuitable candidates, as the detectorsubstance is required to cross-react with flunitrazepam in a beverage.As a result, aromatic substitution at the fluorine substituent wastargeted as being likely to succeed.

An analysis of scientific literature indicated that compoundssubstituted with an amine (—NH) or thiol (—SH) substituent were likelyto react with flunitrazepam in the expected conditions. The theoreticalreaction mechanism is shown below in Scheme I, assuming that thereaction occurs at room temperature in the presence of ethanol as asolvent, where ethanol is present in a mixed drink or cocktail.

Screening of the EAFUS and FRAS databases resulted in the identificationof about 66 compounds comprising 23 primary or secondary amines and 43thiol compounds.

The structure of the adduct resulting from the reaction of eachcandidate with flunitrazepam was generated using a LeadGrow tool forvirtual library generation from VLifeMDS4.3. The generated adducts wereenergy minimized using the MMFF force field until a convergencecriterion of 0.0001 kcal/mol was achieved. The geometry of the resultingenergy-minimized compounds was used to evaluate the predicted flavor andaroma of the generated adducts.

Prediction of Product Taste or Smell

The flavor and aroma of the computationally-generated flunitrazepamadducts were predicted using a QSAR Model. QSARs (Quantitative StructureActivity Relationships) are mathematical models that may be used topredict the physical characteristics of a compound from its chemicalstructure (known as molecular descriptors). In the QSAR model used, thefollowing parameters were used:

TABLE 1 Parameters used to evaluate flavor Model K nearest % Predictionaccuracy No. Descriptors q2 Pred_r2 neighbour (training/test) # 1H-DonorCount 0.94 0.95 4 94/95 k3alpha 6ChainCount HydrogensCount 24ChainCount 0.95 0.84 4 95/84 6ChainCount HydrogensCount slogp SdOcountchiV3chain

TABLE 2 Descriptor Definitions for Table 1 Descriptor DefinitionH-DonorCount The number of Hydrogen bond donors present in the moleculesk3 alpha This descriptor signifies third alpha modified kappa shapeindex 6ChainCount This descriptor gives total number of six memberedrings present in a compound HydrogensCount The number of hydrogen atomspresent in the molecule 4ChainCount This descriptor signifies totalnumber four membered rings in a compound slogp: This is log of theoctanol/water partition coefficient SdOcount This descriptor defines thetotal number of oxygen connected with one double bond chiV3chain Thisdescriptor signifies atomic valence connectivity index for threemembered ring.

TABLE 3 Parameters used to evaluate aroma % Prediction accuracy Model Knearest (training/ No. Descriptors Q2 Pred_r2 neighbour test) # 1T_C_O_2 0.87 0.64 2 87/64 T_2_O_6 T_T_O_6 Epsilon4 T_2_N_1 2 T_2_O_00.83 0.64 4 83/64 chiV4pathCluster DeltaEpsilonA T_2_O_6 SsIE- index

TABLE 4 Descriptor Definitions for Table 3 Descriptor Definition T_C_O_2Number of Carbon atoms separated from Oxygen atom by 2 bonds in themolecule T_2_O_6 Number of double bonded atoms separated from Oxygenatoms by 6 bonds in the molecule T_T_O_6 The count of number of atomspresent at a bond distance of 6 from any Oxygen atom in the moleculeEpsilon4 Measure of electronegative atom count including hydrogen atomswith respect to the saturated hydrocarbon(reference alkane) created fromthe molecule/fragment under consideration T_2_N_1 Number of doublebonded atoms separated from any Nitrogen atom by a single bond in themolecule T_2_O_0 Number of Oxygen atoms with a double bond present inthe molecule chiV4pathCluster This descriptor signifies valencemolecular connectivity index of 4th order pathcluster. DeltaEpsilonA Ameasure of contribution of unsaturation and electronegative atom count

Adducts were subjected to taste and smell predictions using QSAR modelsthat employed the descriptors defined above. The resultant adducts weresorted based upon the reliability of the predictions. The adductsprovided in Table 5 are predicted to have a strong off-taste, while theadducts provided in Table 6 are predicted to have a strong musk smell,which would be unlikely to remain undetected even when the user is underthe influence of alcohol.

TABLE 5 Adducts Predicted to have Strong Flavor Cpd. No. ReagentStructure of Adduct Chemical Name  1

5-[2-(butylsulfanyl)phenyl]- 1-methyl-7-nitro- 1,3-dihydro-2H-1,4-benzodiazepin-2-one  2

1-methyl-5-{2-[(2- methylpropyl)sulfanyl] phenyl}-7-nitro-1,3-dihydro-2H-1,4- benzodiazepin-2-one  3

5-[2-(cyclopentyl- sulfanyl)phenyl]- 1-methyl-7-nitro-1,3-dihydro-2H-1,4- benzodiazepin-2-one  4

5-[2-(dimethylamino) phenyl]-1-methyl-7- nitro-1,3-dihydro-2H-1,4-benzodiazepin- 2-one  5

5-{2-[(2-aminoethyl) amino]phenyl}-1- methyl-7-nitro-1,3-dihydro-2H-1,4- benzodiazepin-2-one  6

5-{2-[(2- hydroxyethyl)amino] phenyl}-1-methyl- 7-nitro-1,3-dihydro-2H-1,4-benzodiazepin- 2-one  7

1-methyl-5-(2-{[2-(4- methylcyclohexyl-3-en- 1-yl)propan-2-yl]sulfanyl}phenyl)-7- nitro-2,3-dihydro- 1H-1,4- benzodiazepin-2-one  8

5-{2-[(2-ethylheptyl) sulfanyl]phenyl}- 1-methyl-7-nitro-2,3-dihydro-1H-1,4- benzodiazepin-2-one  9

5-{2-[(1-methoxyheptan- 3-yl)sulfanyl] phenyl}-1-methyl-7-nitro-2,3-dihydro-1H- 1,4-benzodiazepin- 2-one 10

1-methyl-7-nitro-5-{2- [(3-oxobutyl) sulfanyl]phenyl}-1,3-dihydro-2H-1,4- benzodiazepin-2-one 11

1-methyl-7-nitro-5-[2- (pentan-3-ylsulfanyl) phenyl]-2,3-dihydro-1H-1,4- benzodiazepin-2-one 12

5-[2-(heptylsulfanyl) phenyl]-1-methyl-7- nitro-2,3-dihydro-1H-1,4-benzodiazepin- 2-one 13

4-{[2-(1-methyl-7-nitro- 2-oxo-2,3-dihydro- 1H-1,4-benzodiazepin-5-yl)phenyl]amino} butanoic acid 14

5-[2-(cyclohexylamino) phenyl]-1-methyl-7-nitro- 2,3-dihydro-1H-1,4-benzodiazepin- 2-one

Compounds 1-3 are predicted to possess a strong off-taste by both QSARmodels. Compounds 4-6 are predicted to possess a strong off-taste by oneof the two QSAR models. Compounds 5-6 are also predicted to possess anoff-aroma.

TABLE 6 Adducts Predicted to have Strong Aroma Cpd. No. ReagentStructure Chemical Name 15

1-methyl-7-nitro-5-{2-[(3- sulfanylbutan-2- yl)sulfanyl]phenyl}-1,3-dihydro-2H-1,4- benzodiazepin-2-one 16

1-methyl-5-{2-[(2- methyltetrahydrofuran-3- yl)sulfanyl]phenyl}-7-nitro-1,3-dihydro-2H-1,4- benzodiazepin-2-one 17

1-methyl-5-{2-[(3- methylbutan-2- yl)sulfanyl]phenyl}-7-nitro-2,3-dihydro-1H-1,4- benzodiazepin-2-one 18

5-{2-[(5-{[5-(2-hydroxyethyl)- 4-methyl-2,3-dihydro-1,3-thiazol-3-yl]methyl}-2- methylpyrimidin-4- yl)amino]phenyl}-1-methyl-7-nitro-2,3-dihydro-1H-1,4- benzodiazepin-2-one 19

5-[2-({5,6-dimethyl-2-oxo- 1H,2H-thieno[2,3-d]pyrimidin-4-yl}amino)phenyl]-1-methyl- 7-nitro-2,3-dihydro-1H-1,4-benzodiazepin-2-one 20

4-{[2-(1-methyl-7-nitro-2-oxo- 2,3-dihydro-1H-1,4- benzodiazepin-5-yl)phenyl]amino}butanoic acid 21

5-[2- (cyclohexylamino)phenyl]-1- methyl-7-nitro-2,3-dihydro-1H-1,4-benzodiazepin-2-one 22

1-methyl-7-nitro-5-[2- (propan-2-ylamino)phenyl]- 1,3-dihydro-2H-1,4-benzodiazepin-2-one 23

1-methyl-7-nitro-5-[2- (propylamino)phenyl]-1,3- dihydro-2H-1,4-benzodiazepin-2-one

Compound 15-17 are predicted to possess a particularly strong off-aromaby both QSAR models. Compound 18 is predicted to possess a strongoff-aroma by one of the two QSAR models. Compounds 15-17 are alsopredicted to possess an off-taste.

TABLE 7 Toxicity Data for Selected Detector Substances Sr No ReagentToxic Dose Usage dosage 1 butane-1-thiol gavage-rat LD50 1500 mg/kg 1.00ppm 2 2-methylpropane-1-thiol gavage-rat LD50 7168 mg/kg Not determinedoral-rat LD50 7168 mg/kg 3 cyclopentanethiol oral-mouse LD50 [sex: M, F2.00 ppm (5/group)] 2680 mg/kg 4 N-methylmethanamine oral-rat LD50 698mg/kg — 5 ethane-1,2-diamine oral-rat LD50 1200 mg/kg — oral-mouse LD501000 mg/kg 6 2-aminoethanol oral-rat LD50 1720 mg/kg — 71-p-menthene-8-thiol — — 8 2-ethylheptane-1-thiol — — 91-methoxyheptane-3-thiol — 0.003 mg/kg 10 4-sulfanylbutan-2-one — — 11pentane-3-thiol — 0.020 mg/kg 12 heptane-1-thiol — 0.40 mg/kg 134-aminobutanoic acid oral-mouse LD50 12680 mg/kg 50 mg/kg mouse LD507230 mg/kg 14 cyclohexanamine oral-rat LD50 11 mg/kg — LD50 224 mg/kg 15butane-2,3-dithiol — — 16 2-methyltetrahydrofuran- gavage-mouse LD501860 mg/kg 5.00 ppm 3-thiol 17 3-methylbutane-2-thiol gavage-rat LD50[sex: M, F] 540 mg/kg 2.00 ppm 18 2-{3-[(4-amino-2- — —methylpyrimidin-5- yl)methyl]-4-methyl-2,3- dihydro-1,3-thiazol-5-yl}ethanol 19 4-amino-5,6- — — dimethylthieno[2,3- d]pyrimidin-2-one 204-aminobutanoic acid oral-mouse LD50 12680 mg/kg 50 mg/kg mouse LD507230 mg/kg 21 cyclohexanamine oral-rat LD50 11 mg/kg — LD50 224 mg/kg 22propan-2-amine oral-rat LD50 111 mg/kg 2 mg/kg mammal (speciesunspecified) LD50 500 mg/kg 23 propan-1-amine oral-rat LD50 370 mg/kg 1mg/kg mammal (species unspecified) LD50 580 mg/kg

The following numbered paragraphs describe additional aspects andfeatures of the non-visual indicators and indication methods of thepresent disclosure. Each of these numbered paragraphs can be combinedwith one or more other paragraphs, and/or with disclosure from elsewherein this disclosure, including the materials incorporated by reference,in any suitable manner.

1. A non-visual indication method for the presence of flunitrazepam,comprising:

selecting an ingestible substance;

non-visually indicating whether flunitrazepam is present in theingestible substance by using an indicator, chosen from the groupconsisting of a taste indicator that produces a taste to a user in thepresence of flunitrazepam and a smell indicator that produces a smell toa user in the presence of flunitrazepam.

2. The method of paragraph 1, wherein the indicating step involves usinga taste indicator that produces a taste to a user, wherein the tasteindicator comprises one or more of butane-1-thiol,2-methylpropane-1-thiol, cyclopentanethiol, N-methylmethanamine,ehtane-1,2-diamine, 2-aminoethanol, 1-p-menthene-8-thiol,2-ethylheptane-1-thiol, 1-methoxyheptane-3-thiol, 4-sulfanylbutan-2-one,pentane-3-thiol, heptane-1-thiol, 4-aminobutanoic acid, andcyclohexanamine.

3. The method of paragraph 1, wherein the indicating step involves usinga taste indicator that produces a taste to a user, wherein the tasteindicator comprises one or more of butane-1-thiol,2-methylpropane-1-thiol, cyclopentanethiol, N-methylmethanamine,ehtane-1,2-diamine, and 2-aminoethanol.

4. The method of paragraph 1, wherein the indicating step involves usinga smell indicator that produces a smell to a user, wherein the smellindicator comprises one or more of butane-2,3-dithiol,2-methyltetrahydrofuran-3-thiol, 3-methylbutane-2-thiol,2-{3-[(4-amino-2-methylpyrimidin-5-yl)methyl]-4-methyl-2,3-dihydro-1,3-thiazol-5-yl}ethanol,4-amino-5,6-dimethylthieno[2,3-d]pyrimidin-2-one, 4-aminobutanoic acid,cyclohexanamine, propan-2-amine, and propan-1-amine.

5. The method of paragraph 1, wherein the indicating step involves usinga smell indicator that produces a smell to a user, wherein the smellindicator comprises one or more of butane-2,3-dithiol,2-methyltetrahydrofuran-3-thiol, 3-methylbutane-2-thiol, and2-{3-[(4-amino-2-methylpyrimidin-5-yl)methyl]-4-methyl-2,3-dihydro-1,3-thiazol-5-yl}ethanol.

6. A non-visual verification system, comprising:

a non-visual, sensing mechanism constructed to verify whetherflunitrazepam is present in an ingestible substance by producing anon-visual indicator that can be understood by a user;

wherein the sensing mechanism is constructed to produce an indicator tothe user that is chosen from the group consisting of a taste indicatorand a smell indicator; and

wherein the sensing mechanism comprises one or more of butane-1-thiol,2-methylpropane-1-thiol, cyclopentanethiol, N-methylmethanamine,ehtane-1,2-diamine, 2-aminoethanol, 1-p-menthene-8-thiol,2-ethylheptane-1-thiol, 1-methoxyheptane-3-thiol, 4-sulfanylbutan-2-one,pentane-3-thiol, heptane-1-thiol, 4-aminobutanoic acid, cyclohexanamine,butane-2,3-dithiol, 2-methyltetrahydrofuran-3-thiol,3-methylbutane-2-thiol,2-{3-[(4-amino-2-methylpyrimidin-5-yl)methyl]-4-methyl-2,3-dihydro-1,3-thiazol-5-yl}ethanol,4-amino-5,6-dimethylthieno[2,3-d]pyrimidin-2-one, 4-aminobutanoic acid,cyclohexanamine, propan-2-amine, and propan-1-amine.

7. The system of paragraph 6, wherein the sensing mechanism is alsoconstructed to be concealable so that the user can limit observation ofthe indicator by others.

8. The system of paragraph 6, wherein the sensing mechanism isconstructed to produce a taste indicator to the user and comprises oneor more of butane-1-thiol, 2-methylpropane-1-thiol, cyclopentanethiol,N-methylmethanamine, ehtane-1,2-diamine, 2-aminoethanol,1-p-menthene-8-thiol, 2-ethylheptane-1-thiol, 1-methoxyheptane-3-thiol,4-sulfanylbutan-2-one, pentane-3-thiol, heptane-1-thiol, 4-aminobutanoicacid, and cyclohexanamine.

9. The system of paragraph 6, wherein the sensing mechanism isconstructed to produce a smell indicator to the user and comprises oneor more of butane-2,3-dithiol, 2-methyltetrahydrofuran-3-thiol,3-methylbutane-2-thiol,2-{3-[(4-amino-2-methylpyrimidin-5-yl)methyl]-4-methyl-2,3-dihydro-1,3-thiazol-5-yl}ethanol,4-amino-5,6-dimethylthieno[2,3-d]pyrimidin-2-one, 4-aminobutanoic acid,cyclohexanamine, propan-2-amine, and propan-1-amine.

Although the present invention has been shown and described withreference to the foregoing operational principles and preferredembodiments, it will be apparent to those skilled in the art thatvarious changes in form and detail may be made without departing fromthe spirit and scope of the invention. The present invention is intendedto embrace all such alternatives, modifications and variances that fallwithin the scope of the appended claims.

What is claimed is:
 1. A non-visual verification method, comprising:selecting an ingestible substance; using a detector on the selected,ingestible substance; non-visually indicating whether a target substanceis present in the ingestible substance.
 2. The method of claim 1,wherein the indicating step is non-visually and concealably indicatingwhether a target substance is present in the ingestible substance. 3.The method of claim 1, wherein the using step involves using a tastedetector.
 4. The method of claim 2, wherein the using step involvesusing a taste detector.
 5. The method of claim 1, wherein the using stepinvolves using a touch detector.
 6. The method of claim 2, wherein theusing step involves using a touch detector.
 7. The method of claim 1,wherein the using step involves using a smell detector.
 8. The method ofclaim 1, wherein the using step involves using a sound detector.
 9. Anon-visual verification method, comprising: selecting an ingestiblesubstance; making a detector for non-visual display of whether a targetsubstance is present in the selected, ingestible substance; operatingthe detector and non-visually indicating whether a target substance ispresent in the ingestible substance.
 10. The method of claim 9, whereinthe making step involves making a detector for non-visual and concealeddisplay of whether a target substance is present in the selected,ingestible substance.
 11. The method of claim 10, wherein the operatingand indicating step involves operating the detector, and non-visuallyand concealably indicating whether a target substance is present in theingestible substance.
 12. The method of claim 9, wherein the making stepinvolves making a taste detector.
 13. The method of claim 11, whereinthe making step involves making a taste detector.
 14. The method ofclaim 9, wherein the making step involves making a touch detector. 15.The method of claim 11, wherein the making step involves making a touchdetector.
 16. The method of claim 9, wherein the making step involvesmaking a smell detector.
 17. The method of claim 9, wherein the makingstep involves making a sound detector.
 18. A non-visual verificationsystem, comprising: a non-visual, sensing mechanism constructed toverify whether a target drug is present in an ingestible substance byproducing a non-visual indicator that can be understood by a user. 19.The system of claim 18, wherein the sensing mechanism is alsoconstructed to be concealable so that the user can limit observation ofthe indicator by others.
 20. The system of claim 18, wherein the sensingmechanism is constructed to produce a taste indicator to the user. 21.The system of claim 19, wherein the sensing mechanism is constructed toproduce a taste indicator to the user.
 22. The system of claim 18,wherein the sensing mechanism is constructed to produce a touchindicator to the user.
 23. The system of claim 19, wherein the sensingmechanism is constructed to produce a touch indicator to the user. 24.The system of claim 18, wherein the sensing mechanism is constructed toproduce a smell indicator to the user.
 25. The system of claim 19,wherein the sensing mechanism is constructed to produce of soundindicator to the user.
 26. A non-visual verification device, comprising:a non-visual, sensing component constructed to verify whether a targetdrug is present in an ingestible substance by producing a non-visualindicator that can be understood by a user.
 27. The device of claim 26,wherein the sensing component is also constructed to be concealable sothat the user can limit observation of the indicator by others.
 28. Thedevice of claim 26, wherein the sensing component is constructed toproduce a taste indicator to the user.
 29. The device of claim 27,wherein the sensing component is constructed to produce a tasteindicator to the user.
 30. The device of claim 26, wherein the sensingcomponent is constructed to produce a touch indicator to the user. 31.The device of claim 27, wherein the sensing component is constructed toproduce a touch indicator to the user.
 32. The device of claim 26,wherein the sensing component is constructed to produce a smellindicator to the user.
 33. The device of claim 27, wherein the sensingcomponent is constructed to produce a sound indicator to the user.